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Naunyn Schmiedebergs Arch Pharmacol. 2019 May 6. doi: 10.1007/s00210-019-01647-w. [Epub ahead of print]

A population pharmacokinetic model of intravenous telavancin in healthy individuals to assess tissue exposure.

Author information

1
Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Straße 24, 50931, Cologne, Germany. sami.ullah@uk-koeln.de.
2
Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
3
Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Straße 24, 50931, Cologne, Germany.

Abstract

Non-compartmental analysis of telavancin microdialysis data indicated a sustained exposure in soft tissues and that unbound plasma concentrations were underestimated in vitro. The objective of the present evaluation was to develop a population pharmacokinetic model of telavancin to describe its plasma protein binding, its distribution into muscle, and subcutaneous tissue and to predict pharmacokinetic/-dynamic target attainment (PTA). Total plasma concentrations and microdialysate concentrations (plasma, subcutaneous, and muscle tissue) were available up to 24 h (plasma microdialysate, up to 8 h) post-dose from eight healthy subjects after a single intravenous infusion of 10 mg/kg telavancin. Population pharmacokinetic modeling and simulations were performed using NONMEM. A two-compartment model with saturable protein binding best described plasma concentrations. Plasma unbound fractions at steady state were 23, 15, and 11% at 100, 50, and 10% of the maximum predicted concentrations respectively. Distribution into muscle and subcutaneous tissue was non-linear and described appropriately by one additional compartment each. Based on total plasma concentrations, predicted median (95% confidence interval) values of AUC/MIC (MIC 0.125 mg/L, clinical breakpoint for MRSA) at steady state were 4009 [3421-4619] with a PTA of 96 [78-100] %. The fAUC/MIC in muscle was 496 [227-1232] with a PTA of 100 [98-100] %. The %fT>MIC was approximately 100% in plasma and interstitial space fluid of muscle and subcutaneous tissues up to an MIC of 0.25 mg/L. The model provided a new hypothesis on telavancin plasma protein binding in vivo. Proposed pharmacodynamic targets in plasma and muscle are achieved with currently approved doses of 10 mg/kg daily.

KEYWORDS:

Methicillin-resistant Staphylococcus aureus; Population pharmacokinetics; Probability of target attainment; Saturable protein binding; Skin and soft tissue infections; Telavancin

PMID:
31062064
DOI:
10.1007/s00210-019-01647-w

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